Interventions against degenerative aging

Potential interventions to ameliorate degenerative aging

Ilia Stambler

A long road ahead

The interventions into the degenerative aging process are still in their infancy.1 A long effortful road will yet need to be traveled from basic research on cell cultures and animal models to effective, safe and widely available human therapies.2 Many dangers to human health (such as overdose and overstimulation) and many unsubstantiated false claims yet await on this road, that need to be guarded against as much as possible.3 Yet vast promising research is progressing, especially as regards potential pharmaceutical interventions into the aging process.4,5 Below are some examples.

Targeting Aging with Metformin

On November 28, 2015, the FDA approved the testing of Metformin, a decades-old anti-diabetic (blood sugar reducing) medication (of the biguanide class), as the first drug to treat degenerative aging, rather than particular diseases or symptoms, as a way to prevent general age-associated multimorbidity (postponing the emergence of several age-related diseases and dysfunctions at once).6,7 Though the study concept may be seminal, as of this writing in 2017, sufficient funding for this trial has been lacking.

Anti-aging adjuvant therapy

On November 25, 2015, the FDA approved an adjuvant therapy (the adjuvant MF59, made with squalene oil, developed by Novartis) for a flu vaccine to boost immune response in older persons. This development goes beyond “a drug against a disease” model, but seeks an appropriate regulatory framework to support the underlying health of older persons, using “adjuvant” (i.e. “supportive/additional”) therapy.8

Rapamycin and rapalogs

The immunosuppressant drug Rapamycin, believed to mimic the healthspan-extending effects of calorie restriction (CR-mimetic), has been shown to produce improvements of energy metabolism, and to extend lifespan and delay aging in mice, and was also effective against particular aging-related diseases, such as Alzheimer’s disease, in human studies. Further research is done on Rapamycin’s analogs – the so-called “rapalogs,” potentially with less side effects.9

Blood transfusion

By splicing the circulatory systems of animals (mice) together, via the process of “parabiosis,” young blood was indicated to have rejuvenating effects on old tissues, including the heart, brain, and muscle tissues, with improved strength and cognitive ability. Some of the hypothetical rejuvenating factors included: Notch signaling activators, deactivation of the transforming growth factor (TGF)-β that blocks cell division, oxytocin, and Growth Differentiation Factor 11 (GDF11). In September 2014, a clinical trial by Alkahest in Menlo Park, California, became the first to start testing the benefits of young blood and young plasma in older people with Alzheimer’s disease.10 However, in a more recent evaluation, it was suggested that young blood does not contain rejuvenating substances, but rather the old blood contains pro-aging, growth-inhibiting substances (or toxic waste products) that can accelerate aging in younger animals, and these can be partly diluted or neutralized by the infusions of young blood. The search has begun for such pro-aging, growth-inhibiting substances and ways of their neutralization.11

Senescent cell elimination

A new class of drugs – the “senolytics” capable of eliminating senescent cells and the accompanying pathologies – are being developed, in Mayo Clinic, Rochester, Minnesota, and elsewhere.12 Thus, the combinations of the “senolytic” drugs Dasatinib and Quercetin proved effective against senescent human cells and in a mouse model. Together these drugs were able to reduce senescent cell burden, extend healthspan and improve physical exercise capacity in old mice, reducing their osteoporosis and other age-related pathologies.13 Senescent cells can also be eliminated by immunological means, such as vaccines, antibodies and killer T cells.14

Sirtuin activation and NAD replacement therapy

Resveratrol, a natural polyphenolic compound, among other sources found in red wine, has demonstrated the ability to up-regulate Sirtuin 1 (SIRT1) – an acknowledged prolongevity enzyme15 – important for enhanced stress response, DNA stabilization, cardiovascular protection, improved cognitive function and synaptic plasticity, and suppressing inflammation.16 SIRT1 expression is generally related to the levels of energy metabolism, as indicated by NAD/NADH levels, which have also become targets for diverse pharmaceutical interventions (NAD replacement therapy).17 Additional forms of NAD replacement therapy (e.g. with nicotinamide riboside – NR – a form of vitamin B3, and nicotinamide mononucleotide – NMN)18,19 and activators of other Sirtuin enzymes (such as SIRT6)20,21 are being developed.

pH and Redox manipulation

Dichloroacetate and bicarbonate represent a class of compounds and therapies that may have systemic effects on tissue redox and pH state, with broad implications for the aging process22 and derivative pathologies, such as cancer.23

Generally, regenerative medicine, using stem cells of various origins to rebuild, “regenerate” or improve the function of worn out and aging organs and tissues, can be promising for combating the degenerative pathologies of aging.24 Even entire “replacement organs and tissues” can be grown outside of the body – using such methods as growing tissues on biodegradable scaffolds, 3D tissue printing, bioreactors or self-organization — to “replace” the worn out and aging body parts.25 Yet, recently a very promising direction in regenerative medicine has emerged – the induction of regeneration within the body by pharmacological means (e.g. using inhibitors of prostaglandin breakdown, thus promoting cell proliferation).26

Immune organ regeneration

Of special importance for regenerative medicine against aging-related degeneration is the ability to regenerate the thymus gland (that produces the immune T-cells that play the crucial role for the immune defense). This importance derives from the fact that such an ability could dramatically improve therapy not only for aging-related non-communicable chronic diseases (such as heart disease and neurodegenerative diseases that are strongly related to altered immune response), but also help combat infectious, communicable diseases (like AIDS, Herpes and Influenza) thanks to improved immunity. Such regenerative ability for the thymus was shown by genetic engineering interventions (e.g. using over-expression of the FOXO gene)27 and even pharmaceutical treatments (e.g. using the FGF21 hormone).28

Telomere extension to increase cell replication

The extension of the telomere end points of the chromosomes, thus increasing the number of cell replications, by such means as genetically engineered overexpression of the telomere-repairing enzyme – telomerase, and even by some pharmacological stimulators of telomerase activity, have been associated with increased lifespan and reduced pathology in animal models.29,30

Improving mitochondrial function

There have been many methods investigated for improving mitochondrial function and cellular respiration. Thus anti-oxidant molecules attached to positively charged ions (cations) have been targeted into mitochondria to eliminate oxidative damage at its origin (the SkQ ions).31 In another approach, chemical compounds (in particular suppressors of the IIIQsite of the respiratory chain in the mitochondria) have been identified that can block the production of certain free radicals in cells, without changing the energy metabolism of these cells.32 A large additional array of boosters of mitochondrial activity and cellular respiration has been proposed, e.g. methylene blue, the naphthoquinone drug β-lapachone, supplementation with various components of the respiratory oxidative phoshorylation system – such as CoQ10, pyruvate, succinate, vitamins C and K, quercetin, various other anti-acidic, anti-toxic, and anti-oxidant substances.33

Immune-modulating substances

Anti-inflammatory medications have been widely tested to diminish aging-related degenerative pathologies, such as neurodegenerative pathologies, and to extend healthy lifespan in animal models.34 But also pro-inflammatory effects have been shown to be important for tissue regeneration.35

Cross-link breakers

Diverse means are being developed to dissolve macro-molecular (cross-linked) aggregates that “clog” cell machinery. Some approaches include stimulation of cell autophagy that can help remove such aggregates (e.g. by introducing Beclin protein). Various “AGE-breakers” are being developed. These are, as a rule, small molecules capable of breaking “Advanced Glycation Endproducts (AGE)” that are chiefly responsible for the formation of macromolecular aggregates (such as glucosepane, one of the most common forms of cross-linked AGE products in collagen). Some of the therapeutic means against cross-linked aggregates include chelators (removing the metal ions that are important for the formation of the cross-links), enzymatic clearance (oxidoreductive depolymerization of the aggregates by enzymes), immunoclearance (using immune mechanisms, e.g. antibodies, to remove the aggregates), etc.36,37 Yet, it needs to be noted that macromolecular aggregates, in certain amounts and under certain circumstances, may have a necessary function in the body too.38 Removing too much of them and in wrong places may do more damage than good.

Nutrient balance

Keeping the body chemistry in balance is hoped to be achieved by supplementing deficient elements in the diet (e.g. vitamins, microelements, other essential nutrients), while eliminating excessive and therefore toxic elements (by such means as chelators, enterosorbents, dietary restriction, enhanced elimination).39 But what is “the balance”? How much is “too much” or “too little”? The guiding rule is always: “The dose makes the poison.”1 Dietary interventions, that are being tested, include dietary restrictions of various kinds (mainly protein restriction and calorie restriction) that have been associated with extended lifespan in animal models and some health benefits in humans.40 Also new ways are being sought to enrich the “microbiome” (intestinal bacteria populations) for healthy longevity,41 for example using probiotic diets – the idea that goes back to the origins of scientific aging research, over a century ago.42

Epigenetic rejuvenation

Epigenetics (acquired or heritable changes in gene function without changes in DNA sequence), has been increasingly investigated and manipulated for its effects on aging and aging-related diseases, and their amelioration, at the level of the entire organism as well as particular tissues, for example, using demethylating agents, small interfering RNAs (siRNAs) and micronutrients as potential therapeutic agents.43-45

Nanomedicine

Interventions into degenerative aging are now beginning to reach the “nano” level (using molecular structures and devices up to several hundred nanometers). Some of the uses of nanomedicine against degenerative aging include nanoparticles, such as Buckminsterfullerene or “bucky-ball” C60, with assumed antiviral, antioxidant, anti-amyloid, immune-stimulating and other therapeutic activities, and some reported lifespan-extending results in mice.46 Moreover, there even have been announced the first operating medical nanorobots, mainly intended to assist in precise drug delivery, acting as prototypes of artificial immune cells.47 These nanodevices were mainly intended to eliminate cancer cells, but could also be used to eliminate other types of cells, e.g. senescent cells. In another area of development, oxygenated micro-particles seem to be very promising for life extension, especially in critical conditions, as oxygen deprivation is the main (or even the ultimate) cause of death.48

Physical interventions

Anti-aging and life-extending interventions do not necessarily need to be chemical and biological, but can also be physical, in particular as relates to various resuscitation technologies (hypothermia and suspended animation,49,50 oxygenation,51-53 electromagnetic stimulation54-56). Such technologies represent probably the most veritable means for life extension, demonstrably saving people from an almost certain death. But similar principles could perhaps be used for more preventive treatments and in less acute cases.

Biomarkers of aging

It seems to be impossible to speak of “treating” or “curing degenerative aging” without the ability to diagnose this condition and to reliably assess the effectiveness of interventions against it.2,3,57-59 Hence a wide array of biomarkers and clinical end points are being sought to diagnose degenerative aging and aging-related ill health, and to determine correct “biological age.”60-63 Clinically applicable and scientifically grounded diagnostic criteria and definitions for aging may also have profound encouraging implications for the regulation and promotion of research, development, application and distribution of anti-aging and life-extending and healthspan-extending therapies.64,65

David Blokh, Ilia Stambler, “The use of information theory for the evaluation of biomarkers of aging and physiological age,” Mechanisms of Ageing and Development, 163, 23-29, 2017, doi: http://dx.doi.org/10.1016/j.mad.2017.01.003.